A method for the manufacture of a solid porous separation material based on a polysaccharide, said method comprising the steps of: (a) providing an aqueous solution (I) of a polysaccharide, (b) solidifying the solution, preferably by transforming the solution to a gel, and (c) optionally crosslinking the polysaccharide, with the proviso that, if step (c) is present, steps (b) and (c) may be carried out simultaneously. The method is characterized in that the polysaccharide provided in step (a) is modified by being inter-molecularly crosslinked to an extent such that the viscosity of the solution (I) is at least 110%, preferably at least 200%, of the viscosity of an aqueous solution (II) of the corresponding polysaccharide which has not been intermolecularly crosslinked and which is present in the same concentration as the inter-molecularly crosslinked polysaccharide is in solution (I)

The present invention is a method for the manufacture of a porous material from a polysaccharide. The starting polysaccharide used in the innovative method has been modified such that it will give an aqueous solution (solution I) which has a viscosity that is higher than the viscosity of the corresponding solution (solution II) in which the unmodified polysaccharide is present in essentially the same concentration. Other conditions for solutions I and II are the same.
By the term "unmodified polysaccharide" is meant the polysaccharide or the polysaccharide derivative that has been used to synthesise the modified polysaccharide that has an increased viscosity.
According to previous techniques, processes comprising the steps of:                (a) forming an aqueous solution (I) of a suitable polysaccharide,        (b) solidifying the solution, and        (c) optionally cross-linking the polysaccharide to become insoluble have resulted in porous polysaccharide material. Steps (b) and (c) has been performed simultaneously or in sequence. The term "solidifying" primarily has meant transforming the solution to a gel.
The material so obtained has been used as support matrices in separation methods, such as electrophoresis, chromatographic and batch-mode separations based on adsorption and/or size exclusion, cell culturing (as microcarriers) etc.
This production technology can give beads if the solution is emulsified in an organic solvent, which is not miscible with water (water-in-oil emulsions). By including the proper derivatization reagent in the solution, it will be possible to form inter- as well as intra-molecular cross-links to an extent that will insolubilize the polysaccharide and solidify the drops. An insoluble cross-linked 3-dimensional polymeric polysaccharide network will form. An alternative way to produce beads has been to select a polysaccharide that dissolves in aqueous liquid media when warmed and solidifies to a gel when the temperature of the solution is decreased.
In this variant the polysaccharide may be cross-linked simultaneously or subsequent to the gelling reaction.
In the case the solution is transformed to a gel without prior emulsification monolithic material will form.
Cross-linking is imperative for gel formation in case the polysaccharide is of the kind that lacks or has a too low gelling temperature. Otherwise cross-linking is optional and depends on use.
Cross-linking means that the rigidity of the material will increase which in turn means that the material may be better fitted to uses requiring application of pressure, for instance liquid chromatography.
The pore sizes of the material obtained primarily depend on the concentration of polysaccharide in the solution provided in step (a).
Sometimes monolithic materials with very large pores (macropores or superpores) are desired. Typical large pores have diameters >0.2 μm, such as ≧0.5 μm. In this case one starts with forming an oil-in-water solution where the water phase comprise the polysaccharide. The system is then transformed to a gel by cooling and/or cross-linking in the same manner as for a material with smaller pores. In the case beads with large pores are desired, the oil-in-water emulsion is emulsified into an organic solvent that is not miscible with water, whereafter the aqueous solution is transformed to a gel in the same manner as discussed above. See U.S. Pat. No. 5,723,601 (Amersham Pharmacia Biotech AB), WO 0017257 (Amersham Pharmacia Biotech AB) and WO 0012618 (Amersham Pharmacia Biotech AB).
Alternative ways for producing porous polysaccharide beads include so-called atomisation techniques in which free drops of the polysaccharide solution (solution I) is created. These variants can be illustrated by spraying the solution in an air stream (WO 9702125, FMC Corporation) and WO 0029466, XC Corporation)) or by the so-called spinning disc atomisation (WO 9520620 (Biodev AB)).
Alternative ways include coating of individual solid particles with the polysaccharide solution (solution I) prepared in step (a) followed by solidifying the solution as in step (b) with an optional subsequent cross-linking (step (c)). See for instance WO 9200799 (Upfront Chromatography AS).
WO 9738018 discloses a process for the production of a cross-linked polysaccharide gel. More specifically, this application teaches a method of preactivating an agarose solution to a suitable degree. After such a preactivation, the solution is solidified and the activated group can then be used as a cross-linker to improve the rigidity of the gel.
U.S. Pat. No. 5,827,937 also relates to providing an activated polysaccharide. This is achieved by sterically preventing completion of the cross-linking, whereby an activated polysaccharide is obtained. At a later stage, the polysaccharide is reactivated and the cross-linking is then allowed to proceed to a viscoelastic gel.
Drawbacks of Earlier Techniques
The above-mentioned processes have certain drawbacks. For instance, if one is to incorporate densifying particles by dispersing the particles into the solution, the viscosity of the solution is typically not high enough. The densifying particles will have strong tendency to separate out without being incorporated into the final polysaccharide material. In the case the goal is to produce polysaccharide beads containing densifying particles the portion of beads without densifying material will be unacceptable high. This drawback in particular applies for the kind of beads disclosed in WO 971732 (Amersham Pharmacia Biotech AB) (bead density >1 g/cm3 such as ≧1.2 g/cm3 (in a wet swollen state) and densifying particles with a density ≧3 g/cm3).
It is also likely that viscous compared to non-viscous polysaccharide solutions have advantages in the so-called atomisation techniques. Compare e.g. WO 9520620 (Biodev AB).
These problems can not simply be overcome by conventionally increasing the viscosity by (a) increasing the concentration of the polysaccharide, (b) cooling the solution, (c) adding thickeners etc. Increasing the concentration of the polysaccharide leads to decreased pore sizes, which is a drawback if material with smaller pores is to be produced. Cooling is of limited value due to the fact that most polysaccharides and polysaccharide derivatives precipitates or gels when cooled. Addition of thickeners tends to give inhomogeneities in the final material.
Objects of the Invention
The objectives of the invention are to provide a manufacturing method as defined above in which the above-mentioned drawbacks have been minimised. This in particular applies to the manufacture of beaded material containing one, two, three or more densifying particles bead including coating procedures and the manufacture of beads by atomisation techniques such as spinning disc atomisation and spraying.
The Invention
The invention thus is an improved variant of the method given in the introductory part. The main characterising feature is that the polysaccharide used is inter-molecularly cross-linked to an extent such that the viscosity of solution (I) is at least 110%, preferably at least 200% such as at least 500%, of the viscosity of an aqueous solution (II) of the corresponding polysaccharide which has not been inter-molecularly cross-linked. The concentration of the corresponding polysaccharide in solution (II) is essentially the same as the concentration of the inter-molecularly cross-linked polysaccharide in solution (I).
Accordingly, the present invention provides a method wherein the viscosity of the polysaccharide is influenced or set before the solidification and this can be performed without any effect on the pore size in the final product. Accordingly, the viscosity is set to a predetermined value, as compared e.g. to the above-discussed WO9738018 wherein the viscosity will be a result of the preactivation, which is the main aim. Thus, said WO 9738018 accepts the viscosity obtained for each preactivation, contrary to the present invention, which is directed to obtaining a desired viscosity.
As discussed above the term "corresponding polysaccharide" refers to the polysaccharide or polysaccharide derivative which has been derivatized to an increased viscosity. Derivatisation in this particular context thus includes any side reaction that takes place in parallel with the introduction of inter-molecular cross-links. A typical side reaction is intra-molecular cross-linking.
This kind of derivatization can be accomplished by the aid of a polysaccharide chain association reagent, which typically acts as a cross-linking reagent. In other words this kind of reagents permits formation of bridges between polysaccharide chains thereby making the chains longer and the corresponding solutions more viscous.
There are mainly two kinds of polysaccharide association reagents:                (1) bifunctional reagents (including multifunctional reagents) in which each functional group is capable of reacting directly with a hydroxy group of the polysaccharide or an activated form thereof to give a covalent bond (homobifuctional reagents), and        (2) bifunctional reagents (including multifunctional reagents) in which only one functional group is capable of forming a covalent bond with the polysaccharide while the other functional groups can be activated for reaction after the first function has reacted (heterobifunctional reagents).
Directly reactive functional groups can be illustrated with electrophilic groups such as epoxides; haloalkyl groups such as halohydrins, vicinal dihalides, α-halocarbonyls; activated esters; acid halides etc. In one and the same chain association reagent, the reactive functional groups may be identical or different.
Functional groups in the chain association reagent that require activation of the hydroxy group of the polysaccharide are typically nucleophilic, such as amino, hydroxy etc. Activation of hydroxy groups of the polysaccharides often means transformation to electrophilic groups, for instance of the type given in the preceding paragraph.
Bifunctional reagents of the second type (2) are illustrated by reagents in which                (a) the activatable function is an unsaturation, i.e. a carbon-carbon double or triple bond, and        (b) the other function is represented by groups that are directly reactive with hydroxy in the polysaccharide or an activated form thereof.
The directly reactive group of these reagents can be selected according to the same rules as for the type (1) reagents. Once inserted onto the polysaccharide the groups with a concealed reactivity may be activated, e.g. by halogenation or epoxidation. Alternatively they may be caused to react with each other, for instance via free radical reactions. Typical examples of popular unsaturated groups are alkene groups such as in allyl and in acryl esters, acryl amides and the corresponding methacryl variants.
The intra-molecularly cross-linked polysaccharide provided in step is water-soluble. It is typically based on a native polysaccharide that is water-soluble as such or that has been derivatized to become water-soluble. Derivatization in this context means that groups that are hydrophilic as such or that disturb the native conformation of a water-insoluble polysaccharide have been introduced. Accordingly the inter-molecularly cross-linked polysaccharide may be based on a native polysaccharide such as dextran, agarose, cellulose, starch, pullulan etc. For some kind of porous polysaccharide matrices it is an advantage to use a polysaccharide in step (a) that dissolves in warm water but gels or solidifies upon cooling. Typical examples of this kind of polysaccharides are agarose and certain modified forms thereof, hydroxyalkylated celluloses etc.
Derivatization of native polysaccharides that then can be intra-molecularly cross-linked and used in step (a) means introduction of organic groups such as charged groups (e.g. carboxy groups, sulphonic acid groups, ammonium groups), neutral groups that may be hydrophilic (e.g. hydroxy lower alkyl groups and lower alkyl groups) etc. By lower alkyl is typically meant C1-3 alkyl groups (methyl, ethyl, propyl) or any other alkyl group that introduces the desired properties on the native or derivatized polysaccharide.
The degree of cross-linking in the polysaccharide that is provided in step (a) should be such that the polysaccharide is water-soluble at the temperature used for producing solution (1). This means that the conditions and reagents used for its synthesis should be selected such that unacceptable amounts of inter- and intra-molecular cross-links are not formed.
A suitable quality of a polysaccharide for step (a) may be obtained by using a very low amount of chain association reagent compared to the amount of polysaccharide. If the amount is too high the risk for quick insolubilization becomes significant. The actual amount will depend on factors such as molecular weight of the reagent, its reactive groups and their ability to participate in side reactions, the amount of polysaccharide etc. There are advantages in monitoring the proceeding of the reaction by the measurement of the change in viscosity and stopping the reaction when the desired viscosity has been obtained. See the experimental part for a general guideline how to control the synthesis.
It has been found that the concentration of the inter-molecularly cross-linked polysaccharide required for predetermined porosity may be essentially the same as the concentration of the corresponding non-cross-linked polysaccharide. This gives practical advantages since the concentrations of the polysaccharide that is provided in step (a) can be set according to well-established practice while at the same time avoiding the drawbacks discussed above.
Porosity values and/or pore sizes of polysaccharide matrices are often expressed as exclusion limits in terms of how large portion of the material a particular compound can utilise (Kav). See Hagel in "Protein Purification, Principles, High Resolution, and Applications", J-C Janson and L Rydén (Eds), VCH Publishers Inc. New York, 1989, p. 99. Typical Kav values are within the interval of 0.10–0.95 and may depend also on further derivatization of the material, for instance introduction of so-called extenders (WO 9822572, Amersham Pharmacia Biotech AB). This means that for the matrix as it is obtained in step (c), the typical interval is somewhat narrower such as 0.40–0.95.
The polysaccharide material will always contain so-called smaller pores (micropores) in which mass transport is taking place by diffusion. In addition there may also be present larger pores (macropores or superpores) in which mass transport can take place by convection. The size range for the micropores is typically 20–5000 Å and for the superpores 0.5–100 μm. For material in form of porous beads, the ratio between the pore diameters of the macropores and the bead diameter typically is in the interval 0.01–0.3, with preference for 0.05–0.2. The ratio between the pore diameters of the micropores may in the preferred variants extend up to 0.05 but is otherwise below 0.01.
See for instance WO 0017257 (Amersham Pharmacia Biotech AB), WO 0012618 (Amersham Pharmacia Biotech AB) and WO 9319115 (Amersham Pharmacia Biotech AB).
The material can be in form of a population of porous beads or a porous monolith.
The mean bead diameter may vary depending on the use but as a general rule is within the interval of 1–1000 μm, preferably 1–50 μm for high performance applications and 50–300 μm for preparative purposes. A population of beads produced may be mono disperse (monosized) or poly dispersed (polysized). By a mono disperse population of beads is contemplated that more than 95% of the beads have diameters (hydrodynamic diameters) within the mean diameter of the population ±5%. The manufacture of beads having a certain mean bead diameter and bead size distribution is done according to established practice.
Beads having densities above about 1 g/cm3 (in a wet swollen state) are used in separation methods involving adsorption to beads that have been fluidised by an upward liquid flow. The liquid then typically is aqueous with a density around 1 g/cm3. This kind of beads may be produced by the aid of the present invention which then means that densifying minor particles are dispersed into the aqueous solution prepared in step (a) whereafter the solution is made into drops that are allowed to solidify. There may be one, two or more filler particles per bead. A produced population of beads may have a distribution of densifying particles in the beads or the same number of densifying particles in each bead. The densifying particles may be porous or non-porous. This kind of beads have been described in WO 9218237 (Amersham Pharmacia Biotech AB); WO 9717132 (Amersham Pharmacia Biotech AB); WO 9833572 (Amersham Pharmacia Biotech AB); and WO 9200799 (Kem-En-Tek/Upfront Chromatography A/S). This kind of beads may also be produced by so called atomisation techniques that have been discussed in general terms above. Beads not having the desired density are removed, for instance beads lacking or having too many densifying particles.
According to the invention this kind of heavy polysaccharide beads may also be prepared by coating individual densifying particles by the polysaccharide solution provided in step (a). After coating the solution is allowed to solidify (step (b)). The densifying core particle may be porous in order to accomplish beads with large surface area. See U.S. Pat. No. 5,837,826 (Flickinger et al).
The densifying particles are in most cases based on inorganic material for instance glass, quartz, metal, metal alloy, metal salts etc. Typical densities of the particles are ≧1.5 g/cm3. See WO 9218237 (Amersham Pharmacia Biotech AB) and WO 9717132 (Amersham Pharmacia Biotech AB). The latter explicitly discloses densifying material that is below and above, respectively, 3 g/cm3 (but always above 1 g/cm3). The relative amount of the densifying material may vary depending on the use of the end product, but typically it constitutes from a 1–5% up to about 70% based on volume per volume. For coated densifying particles the particle may constitute up to 90–95% of the total bead volume.
The material may be derivatized to contain functional groups (ligands) that are used in an adsorption method to bind a desired substance to the material. Functionalization is typically taking place after step (c), but may if the ligand does not to any significant negative extent interfere with steps (a) through (c) be done before step (a). Typical ligands are members of so called affinity pairs, more particular bio-affinity pairs.
Well-known affinity pairs (ligand-receptor pairs) are                (a) oppositely charged entities (ion exchange groups; the immobilised entity being selected among primary, secondary, tertiary and quaternary ammonium, sulphonate, sulphate, phosphonate, phosphate, carboxy etc groups),        (b) antibodies and antigens/haptens,        (c) lectins and carbohydrate structures,        (d) IgG binding proteins and IgG (Protein A and lgG, Protein G and IgG etc),        (e) pair of hydrophobic groups,        (f) chelators and chelates,        (g) complementary nucleic acids,        (h) cells and cell binding ligands,
Affinity members also include entities participating in catalytic reactions, for instance enzymes, enzyme substrates, cofactors, co-substrates etc. Members of cell-cell and cell-surface interactions and a synthetic mimetic of bio-produced affinity members are also included.
A further kind of ligands is able to create reversible covalent bonds during the adsorption step, for instance by containing so called reactive disulphides, —S—SOn— where n is an integer 1 or 2 and the free bonds bind to saturated and/or unsaturated and/or aromatic carbons.
Step (b) above is carried out by any of the known techniques for preparing porous monoliths or population of beads from polysaccharide solutions. Thus monoliths may be obtained simple by cross-linking the intra-molecularly polysaccharide dissolved the solution (I), or, if macroporous materials are desired, by first forming an inverse emulsion from the solution.
Material in beaded form may be obtained by emulsifying the solution in an organic solvent not miscible with water before solidification of the solution. In the alternative, atomisation techniques or conventional coating procedures of particulate material are applicable as well. See above.
For more details of applicable techniques, see the publications discussed above.
The invention will now be illustrated in the experimental part giving proof of principle. The invention is further defined in the appending claims.

Manufacturing process for porous material


Baby and toddler sunglasses comprising frames having lenses. The frames are secured around the user's head by a band. The band is secured to the frames by a securing piece.

Parents try everything to protect their babies and children from the effects of the sun. They are always putting sunscreen on their children, but how do you protect your child's eyes. Babies and toddlers do not want to where sunglasses, and can just remove them after they are placed on the child by the parent.
Eyewear is used for either protective, prosthetic or aesthetic purposes. Eyeglasses consist of a transparent portion encased in a frame that fits around a user's eyes. The transparent portion may be optically inert or include corrective lenses to improve vision. The glasses may be darkened and coated with a radiation filtering film for comfort and protection from sunlight. Frames vary in shape and material.
U.S. Pat. No. 5,771,500 relates to a headband with a lens piece. Incorporated within the headband are a pair of cutouts and a retainer pocket for insertion and retention of a lens piece. The lens piece comprises a pair of eyeglasses with temple pieces removed. A fabric section with a pair of cutouts is attached to the bottom edge of the headband forming the retainer pocket. The headband encircles the head of the wearer and fastens adjustably with releasably cooperating fastener.
U.S. Pat. Nos. D466,543, D432,556, D178,328 and D450,744 relate to different designs for eyewear, sunglasses and eye goggles.
U.S. Pat. No. 2,110,332 relates to a facial protective device. The device is arranged to engage against the face of the wearer and particularly the portions across under the eyes, is a perspiration-absorbent pad, i.e., a sheet having openings for vision and adapted to lie under the goggle cups.
U.S. Pat. No. 5,042,094 relates to eyewear with prosthetic parts for small children. A rigid shatterproof lens portion is encased in a padded and pliable frame that is strapped around the baby's head. Nose and temple pieces are incorporated into the frame to provide support for the frame on the baby's face in the absence of the normally supportive bone structure of adults.
U.S. Pat. No. 5,268,710 relates to sunglasses for infants and small children formed of a lens-defining member made of a thin flexible light-transmitting plastic material of a sun-protective composition or color. The lens-defining member has opposite projecting tabs to which flexible extendable strips are attached for supporting the sunglasses on the head of the wearer. A frame made of a soft flexible plastic foam material and having two superimposed frame members of substantially the same shape is formed by affixing each frame member to a respective face of the lens member.
U.S. Pat. No. 5,718,002 relates to a eye and ear protective eyewear comprising a standard pair of conventional reading glasses, prescription glasses, safety glasses or sunglasses to which a pair of wind deflecting deflectors are attached to the lenses and/or frame and extend rearward from the lenses towards the ear. The deflectors are configured and arranged to deflect air flow away from the ear.
U.S. Pat. No. 5,274,847 relates to a device to protect the wearer's nose from sunlight, to be attached to glasses or goggles. The device is constructed from a single piece of flexible, creasable sheet material, and has a nose shield and a strap extending from the top of the nose shield. The strap is looped over the bridge of the eyewear and threaded through an aperture at the top of the nose shield.
U.S. Pat. No. 5,339,119 relates to an eye protection device comprising a foam rubber-like resilient insert member. There are apertures in the device for receipt of the lenses and frame of a pair of eyeglasses.
U.S. Pat. No. 5,184,156 relates to glasses with color switchable multi-layered lenses. The glasses are for blocking harmful radiation and include a rim connected to temples. The rim contains a photosensor, a color-changing switch, a dry cell power source, solar cells and an electronic driver unit and an electronic circuit. The color-switchable lenses comprise glass plates, and conductive layers and color polarizers, alignment layers, a neutral polarizer, and liquid crystal layers.
U.S. Pat. No. 5,483,303 relates to spectacles having adjustable temples and ear engaging members. The spectacles can be adjusted to accommodate the size and contour requirements of any wearer and includes an eye shield attached to an eye shield frame. The eye shield frame has a groove for receiving a coin or similar object which is used to forcibly dislodge the shield from the shield frame to allow for replacement of the shield.
U.S. Pat. No. 5,541,677 relates to spectacles having a retaining strap with connect earplugs. The device includes an eyeglass retainer for holding eyeglasses on the user's head or around the neck, and earplugs connected to the retainer for protecting the user's hearing.
U.S. Pat. No. 4,715,702 relates to a structure for providing a decorative pattern over the surface of sunglasses, the structure combining a positive decorative pattern on a first layer, a reflective layer, and a third layer incorporating a negative decorative pattern. The decorative pattern is readily apparent to an observer, but the negative pattern cancels the image for the wearer who then sees only a uniform color or hue that does not interfere with the vision of the user.
U.S. Pat. No. 5,359,370 relates to multi-component eyewear. Its features include a 180 degree reflex spring hinge, a sway hinge mechanism that allows the temples to be independently adjusted to improve comfort and fit of the eyewear behind the ears, a strap-pad designed to fit different shaped and sized noses and be positioned for wearer comfort. The device further comprises a frame and lens construction that allows for modularity by the easy removal and replacement of the lens, temples, tops of frames, and nose pieces; and accessories that can be added to the eyewear to provide a greater degree of comfort and to protect the face from ultraviolet radiation and the wind.
U.S. Pat. No. 5,652,635 relates decorative eyeglasses having a lens-carrying frame and temple pieces mounted to the lens carrying frame, the temple pieces including a temple block hinged to the frame, ear pieces, and, between the block and the ear pieces, a segment mounted on the hinge block, but rotatably mounted with respect to the frame. The rotatable section can be made in various shapes, or imprinted with various different decorations on different sides, or made varicolored.
U.S. Pat. No. 5,528,320 relates to protective eyewear having a unitary brow bar with temples and flexible molded hinges. The temples may be adjusted in length. The frame includes integrally molded flexible hinges which allow the temples to collapse. A unitary spherical lens is selectively attached to the frame and can be adapted to wrap around the forehead of the user's temples and include a nose bridge for supporting the lens on the user's nose. A stabilizing strip may be used to hold the frame and lens in place when the eyewear is assembled.
U.S. Pat. No. 6,481,846 relates to a headset and eyewear combination comprising a headset adapted to cover the ears of a user and having a portion of a fastener on the exterior surface of the headset. Eyewear is selectively secured to the exterior portion of the headset with a complimentary portion of the fastener. The eyewear is maintained over the face of the user by means of flexible temples.
U.S. Pat. No. 5,712,697 relates to a pliable sun shield accessory for eyeglasses which includes a pliable elongated tubular member which is formed with a longitudinal slit. The slit allows the elongated tubular member to be splayed apart for positioning over the top portion of the eyeglasses.
U.S. Pat. No. 6,023,372 relates to a light weight, compact remountable electronic display device for eyeglasses or other eye frames. The device attaches to eyewear having a deadborne frame to provide an image from an image display superposed on the ambient image. The display device has a housing which removably mounts to the head-borne frame at a location outside of a user's field of view. An electronic imaging assembly is supported by the housing assembly outside of the user's field of view and in communication with circuitry within the housing assembly to produce an image. An optical element is provided comprising a transparent fixture supporting an eyepiece assembly in front of a user's eye. The transparent fixture is located to receive the image from the electronic imaging assembly and relays the image to the eyepiece assembly, which directs the image to the user's eye.
U.S. Pat. No. 6,062,689 relates to a mechanism for protecting the eyes from the sun that allows a user's temples and face to be exposed completely to the sun by providing a mechanism that includes a sunshield, having a sun-protection factor, an arm attached to a stationary object for selectively positioning and maintaining the sun-shield in front of the eyes, and a mechanism for varying the sun protection factor.
U.S. Pat. No. 6,481,059 relates to hat fasteners for eyeglasses. The invention relates to safety glass holders and eyeglass holders for securing to hats or fabric comprising a wedge shaped design, a clip on design and a fastening design. The fastening design comprises a frame secured to the insides of a hat, first and second elastic cord or pin penetrating the hat and secured to the frame, and a strip disposed between the first and second elastic cords or pins for holding the arm of a pair of safety glasses.
U.S. Pat. No. 6,340,227 relates to an earplug system for storing and dispensing earplugs to an individual. The earplug system includes a connector formed for removably connecting to the distal ends of the arms of glasses, a recoil device attached to the connector, a length of cord stored within and dispensed from the recoil device, and an earplug attached to the cord.
U.S. Pat. No. 6,010,216 relates to a hear speak two-way voice radio communications eyeglasses. The eyeglasses include a radio receiver, a radio transmitter, power supply, antenna and earphones. The receiver, transmitter, power supply, and antenna are within the bow pieces.
U.S. Pat. No. 6,349,001 relates to an eyeglass interface system which integrates interface systems within eyewear. The system includes a display assembly and one or more audio and/or video assemblies mounted to an eyeglass frame. The display assembly is mounted to one temple and provides an image which can be viewed by the user. The audio or video assembly is mounted to the other temple and is in communication with the display assembly. The system may comprise a camera assembly, and/or an audio input or output assembly, such as a microphone and/or speakers. A head tracking assembly may be provided to track the position of the user's head. The system can comprise a telephone system, pager system or surveillance system.
U.S. Pat. No. 6,301,367 relates to wearable audio system with acoustic modules. The acoustic modules are adapted to be worn on the head of a wearer, such as with a headband, or fastened to a hat or eyeglasses. The modules are situated on opposite sides of the wearer's head, adjacent the ears, and each contains a transducer, an outlet port, and a vent port. The audio system is connected to, or in communication with, a conventional source of audio signals, such as radio, tape player, CD player, cellular telephone, or the like.


Oxidized compounds are produced in a continuous integrated process in liquid phase, which comprises: Step I, synthesis of non acidic hydrogen peroxide solutions by direct reaction between hydrogen and oxygen by catalytic reaction utilizing a noble metal catalyst. Step II, this hydrogen peroxide solution is directly mixed with an organic substrate, a suitable catalyst and optionally a solvent. The integrated process requires no treatment step and is particularly well adapted to the production of propylene oxide.

The invention refers to on integrated process for selective oxidation of organic compounds, in liquid phase, which comprises a first step for direct synthesis of a non acidic hydrogen peroxide solution and a second step for oxidation an organic substrate with the reaction mixture of the first step.
Selective oxidation reactions are a major class of chemical transformations which account for the production of a wide variety of important chemical products, including alcohols, carbonyl compounds, epoxides, hydroxylates, acids, glycols and glycol ethers, lactones, oximes, and oxygenated sulfur and nitrogen compounds such as sulfoxides, sulfones, nitrones, azo compounds, and other N-oxides. Performing these chemical transformations efficiently, economically, and safely requires a suitable oxidizing agent which can be purchased or produced to react with the desired organic chemical feedstock, which is then converted to the oxidized organic chemical product.
Several significant problems face conventional oxidation processes. Some industrial processes use gas containing oxygen such as air or pure oxygen. But using oxygen combined with organic chemical feedstocks may accidentally achieve gas compositions in the explosive range, thereby posing a serious safety hazard. Such oxidation processes can also be prone to forming explosive gas mixtures. Oxidative processes using oxygen or air also tend to suffer from product selectivity problems related to over-oxidation of the organic chemical feedstock, normally producing undesired carbon oxides (CO, CO2)
An attractive alternative to using oxygen or air as the oxidation agent is the use of organic hydroperoxides as oxidizing agents. These hydroperoxide compounds, typically generated by oxidation of suitable intermediates with air or O2, are reacted with chemical feedstocks to form oxygenated products and organic by-products. The most common processes for producing propylene oxide (PO) use tert-butyl hydroperoxide and ethylbenzene hydroperoxide as hydroperoxides. These processes cause the formation of a higher quantity of co-products of commercial interest with respect to PO. For example, the process via tert-butyl hydroperoxide co-produces 2.5-3.5 kg of tert-butyl alcohol per kg of PO, whereas via ethylbenzene hydroperoxide co-produces 2.2-2.5 kg of styrene per kg of PO. The presence of these co-products can be of little advantage if the request for PO and the respective co-products is not suitably balanced. For example, when the demand for styrene, or methyl tert-butyl ether (MTBE) which could be obtained from tert-butyl alcohol, is high, the economics of this process are competitive; otherwise these processes are not economic.
Instead of using organic peroxides, hydrogen peroxide is a known desirable oxidizing agent. The byproduct of oxidation reactions using hydrogen peroxide is typically water, a safe compound that can be easily recovered and reused or disposed. The amount of water on a weight basis is much less than the amount of organic by-product when organic hydroperoxides are used, and thereby represents significant savings in process costs. However, past attempts to develop selective chemical oxidation processes based on hydrogen peroxide have encountered significant difficulties. Conventional hydrogen peroxide production utilizes the anthraquinone process, wherein the anthraquinone is first hydrogenated to anthrahydroquinone and then autoxidized to release hydrogen peroxide and the anthraquinone for recycle. Hydrogen peroxide is generated at low concentrations in the solution, and very large flows of anthraquinone and anthrahydroquinone must be handled in order to produce the desired hydrogen peroxide product. Accordingly, such conventionally produced hydrogen peroxide is generally too expensive for commercial use as an oxidizing agent for selective chemical oxidation processes.
A second method for the production of hydrogen peroxide comprises the use of secondary alcohols such as isopropanol and methylbenzylalcohol (U.S. Pat. No. 2,871,102, EP 378388, EP 1074548) or high-boiling secondary alcohols such as diaryl methanol (U.S. Pat. No. 4,303,632) with oxygen. These known processes, however, substantially suffer from disadvantages deriving from the necessity of operating at high reaction temperatures (generally ranging from 100 to 180xc2x0 C.), the partial oxidation of the ketone which is formed as main co-product, the necessity of using a hydrogen peroxide stabilizer (orthophosphoric acid or sodium pyrophosphate). Furthermore, these processes are complicated by the necessity of separating and recovering the cetone and by products from the reaction mixture after using the hydrogen peroxide solution in a subsequent epoxidation process.
An important alternative is generating hydrogen peroxide directly by the catalytic reaction of hydrogen and oxygen, which avoids the difficulty of accompanying large flows of a working solution and can reduce the cost of hydrogen peroxide. These processes generally use a catalytic system consisting of a noble metal, particularly metals of the platinum group or their mixtures, in the form of salts or as supported metals, by reacting the two gases in a solvent consisting of an aqueous medium or an aqueous organic medium. The prior art includes a number of catalytic technologies which directly convert hydrogen and oxygen to hydrogen peroxide, but generally utilize a hydrogen/oxygen feed wherein the hydrogen concentration is greater than about 10 mol % (U.S. Pat. Nos. 4,681,751, 4,772,458, 4,832,938, 5,338,531), which is well above the flammability limit of 4.5 mol % for such mixtures and creates a serious process hazard. At hydrogen feed concentrations below 4.5 mol %, the prior art catalysts are not sufficiently active and selective to generate hydrogen peroxide product at a reasonable rate (WO 99/41190, WO 01/05498 WO 01/05501, U.S. Pat. No. 6,168,775 B1). The prior art technologies need the use in the reaction medium of high concentrations of promoters, for example acid promoters, halogenated products and/or other additives. This makes it necessary to add stabilizers, with onerous purification operations of the H2O2 solution before its use in the oxidation reactions.
Various oxidation processes for organic chemical feedstocks utilizing hydrogen peroxide are known. For example, U.S. Pat. No. 4,701,428 discloses hydroxylation of aromatic compounds and epoxidation of olefins such as propylene with H2O2 using a titanium silicalite catalyst. Also, U.S. Pat. Nos. 4,824,976; 4,937,216; 5,166,372; 5,214,168; 5,912,367, WO 94/238234 and WO 99/48884 all disclose epoxidation of various olefins including propylene using titanium compounds catalysts.
EP 978316 describes a process for catalytic oxidation of an organic compound selected from olefins, aromatic hydrocarbons, ammonia and carbonyl compounds, including a first step for direct synthesis of hydrogen peroxide using a metal of group VIII supported on activated carbon functionalized with sulfonic acids, and a second step for oxidation of said organic compound substrate with the reaction mixture from the first step containing hydrogen peroxide to obtain the desired oxidized product. When the olefin is propylene, the best overall yield of propylene oxide, based on hydrogen feed, that can be achieved is 83%. However, higher yields of oxidized organic compounds are much desired.
U.S. 2001/0016187 describes a process for selective oxidation of organic chemical feedstocks utilizing directly produced hydrogen peroxide intermediate oxidant, including a first step for direct synthesis of hydrogen peroxide using a supported phase-controlled noble metal catalyst, namely a Pd/carbon black catalyst, in a solvent, in the presence of acid promoters and/or stabilizers, such as sulfuric acid, and a second step for oxidation of said organic compound substrate with the reaction mixture from the first step containing hydrogen peroxide to obtain the desired oxidized product. No data concerning oxidation of any organic chemical feedstock is provided.
The present invention provides an integrated process for the oxidation of organic compounds comprising the following steps: Step I, production of hydrogen peroxide from hydrogen and oxygen in the presence of a solvent and a catalyst comprising at least a noble or semi-noble metal supported on a halogen free acid resin; and Step II, wherein the hydrogen peroxide solution is directly mixed with an organic substrate, a suitable catalyst and optionally a solvent to produce the corresponding oxidized compound. The integrated process requires no treatment step and is particularly well adapted to the production of propylene oxide.
FIG. 1 provides an overview of a preferred embodiment of the continuous, integrated process of the invention. The scheme for organic compounds oxidation, using hydrogen peroxide generated by direct reaction of oxygen and hydrogen is illustrated in the Figure. In the first step hydrogen and oxygen (as purified oxygen or air) are reacted over the supported noble metal catalyst in the presence of a liquid solvent in a first reactor or in a first chamber of a twin-chambered tank reactor to generate a liquid solution of hydrogen peroxide. The reaction mixture resulting from this first step is combined, in the second step of the process, in a second reactor or in a second chamber of a twin-chambered tank reactor, with an organic compound which undergoes oxidation.
The reaction mixture from the second step is then fractionated by any of the means that are standard within the art. As a result of the fractionation, unreacted organic compound may be purified and recycled back to the corresponding reactor or chamber. The fractionation process may also provide for isolation of the solvent used in the hydrogen peroxide synthesis. Such fractionation may be employed as a secondary procedure, or as an integral part of the product purification (as illustrated in FIG. 1). This solvent isolated in the fractionation procedure may be recycled for further use.
The figure portrays reagents within boxes, and reactions within elipses. The arrows indicate ingredients required and/or generated by the individual steps of the procedure. The major reagents and reactions are shown in bold typeface, as are the arrows depicting the major additions (ingredients required) and products (ingredients generated) associated with the individual steps of the process.
The present invention provides an effective process for selective oxidation of organic chemical compounds with directly produced hydrogen peroxide, comprising the following steps:
(i) preparing a non acidic hydrogen peroxide solution by reacting hydrogen and oxygen in a solvent, in the presence of a first catalyst comprising at least a noble metal or semi-noble metal belonging to groups VII to XI of the periodic table supported on a halogen-free acid resin:
(ii) recovering the reaction mixture of step (i) containing said non acidic hydrogen peroxide solution; and
(iii) contacting said non acidic hydrogen peroxide solution with an organic chemical compound, in the presence of a second catalyst to render an oxidized product.
The reaction solution of the first reaction (hydrogen peroxide synthesis) may be used directly as a reagent for the second reaction (oxidation). There is no requirement for purification or enrichment of intermediates, or for the removal of by-products from the production of hydrogen peroxide. The second reaction uses the products of the first reaction to oxidize an organic substrate at moderately elevated temperature and pressure. This oxidation reaction is performed in the presence of suitable catalysts. The oxidized product may be recovered from the reaction medium of the second reaction.
The expression xe2x80x9cnon acidic hydrogen peroxide solutionxe2x80x9d, as used in the present description, means that although a catalitical amount of an acid promoter, e.g. HBr, is used in the direct synthesis of hydrogen peroxide from hydrogen and oxygen in a solvent, said compound is added in an amount such that is not sufficient to render acidic the pH of the resultant hydrogen peroxide solution.
According to the present invention, the coupled hydrogen peroxide generating reaction and oxidation reaction may be performed in a continuous manner, using on appropriate reactor, such as, a twin-chambered tank reactor for example, permitting controlled addition of the hydrogen peroxide containing reaction mixture from the first reaction (in the first chamber) into a second chamber. This second chamber would house the oxidation reaction, with forced mixing of the contents and agitation therein of a suspension of catalyst particles. Reactant solutions may be added in combination or sequentially. For example, either the reaction mixture generating hydrogen peroxide, or the organic chemical compound, for example an olefin, or both of these reagents may be added to the reactor incrementally.
The oxidation product may be separated from the oxidation reaction mixture by standard methods known in the art, such as liquid-liquid extraction, extraction by distillation or fractional distillation. These operations may be performed on the entire reaction mixture, and may follow removal of said second catalyst. Alternatively, the oxidized product may be separated from part or all of the reaction mixture according to a periodic program, or from a part of the reaction as a component of a continual operation.
Other components of the oxidation reaction mixture may be isolated by recognized means of fractionation, such as differential distillation, either as part of the process of purifying the product or as a distinct fractionation procedure, preceding or following removal of the oxidized product. The solid catalyst may be separated from the oxidation reaction mixture for regeneration by methods well known in the art, such as filtration. Regeneration of the catalyst is described in greater detail below.
The integrated process for the industrial oxidation of organic compounds that is provided by the invention solves a similar problem to that addressed, in part, by the integrated procedures disclosed in the prior art as described above. In addition, the present invention incorporates improvements to the component reactions of the integrated process which increase their rate, selectivity and compatibility, resulting in significant enhancement of the process as a whole. Certain of these improvements, such as the use into the peroxide-generating reaction of halogen-free acidic resin supported noble metal catalyst can get non-acidic hydrogen peroxide solutions which can be used directly in the oxidation reaction step without any purification or additive feed benefit the overall efficiency of the integrated process.
In particular, the distinctions that differentiate the present invention from U.S. patent application No. 2001/016187 which also discloses an integrated process for oxidizing organic feedstocks, illustrate significant advantages of the present invention:
i. By improving the activity of the peroxide-generating reaction the present invention permits greater concentrations of hydrogen peroxide to be generated in the first reaction mixture which is then used as oxidant solution for the oxidation reaction. The overall yield and efficiency of the process may therefore be increased, provided that the hydrogen peroxide at these elevated concentrations can be maintained in solution by the selected organic solvent and can be prevented from reacting with other components of the reactions making up the integrated process. The current invention successfully addresses each of these requirements.
ii. High concentrations of acid promoters such as inorganic acids (sulfuric, phosphoric, nitric, . . . ) or organic acids (per example, sulphonic acids) are not required in the hydrogen peroxide generation reaction, avoiding the production of acidic hydrogen peroxide solutions that are corrosive and require the use of special equipments.
iii. The ability to use the reaction mixture from the first step directly as an ingredient of the second reaction, providing the peroxide for the oxidation, permits great advantages in efficiency and cost-effectiveness, since no intermediate step is required in order to purify or neutralize the peroxide.
Hydrogen peroxide synthesis and oxidation steps will be described in a detailed manner below.
Hydrogen Peroxide Synthesis Step
In this step, hydrogen and oxygen (as purified oxygen or air) are reacted continuously over the supported noble metal or semi-noble metal catalyst in the presence of a liquid solvent in a reactor to generate a liquid solution of non acidic, hydrogen peroxide. The reactor may contain a fixed, fluidized or slurried bed of the catalyst. The liquid medium may be water, or a suitable organic solvent such as an alcohol, for example, a C1-C12 alcohol, a C1-C12 glycol, or mixtures thereof. Suitable organic solvents can include various alcohols, aromatics, and esters, or any other organic compound that is inert in reaction conditions. Solvents are preferably water-soluble alcohols such as methanol, ethanol, n-propanol, isopropanol, tert-butanol, isobutanol and mixtures thereof. In a particular embodiment, the solvent is selected from the group formed by water, C1-C12 alcohols, C1-C12 glycols, and mixtures thereof. The hydrogen concentration in the reactor is maintained below the flammability limit of about 4.5 mol %. The liquid-phase concentration of hydrogen peroxide intermediate product can vary over a useful range of 1-30 wt %. The optimum hydrogen peroxide concentration depend on a variety of factors, including hydrogen cost, separation requirements, and optimal peroxide concentration for best performance of the downstream oxidation reactor. In general, the preferred H2O2 concentration will be 1-25 wt %, and more preferably will be 5-20 wt %.
The catalyst used in the first step is a halogen-free acidic resin-supported noble or semi-noble metal catalyst that selectively produces essentially only the hydrogen peroxide intermediate, as disclosed in our pending European patent application No. 02380057.6. The halogen-free acidic resin supported noble metal catalyst has been experimentally proved to directly produce hydrogen peroxide at very high selectivity. By using this catalyst in a reactor and at reaction conditions of xe2x88x9210xc2x0 C. to 100xc2x0 C., preferably 10-75xc2x0 C., at a pressure above atmospheric pressure, typically comprised between 2 and 30 MPa, optionally in the presence of an inert gas, the process first reaction step will produce hydrogen peroxide intermediate at very high selectivity, typically, equal to or higher than 80%.
The molar ratio hydrogen/oxygen can vary in a brood range and is preferably comprised between 1/1 and 1/100, more preferably between 1/10 and 1/50.
The support employed in the catalyst used in the process of this invention comprises a resin functionalized with halogen-free acid groups. Preferably, the resins used in the preparation of the catalyst to be used in the first reaction are formed by homopolymerization of monomers or copolymerization of two or more monomers. Examples of resins suitable as a support in the present invention include styrenic, acrylic, methacrylic polymers or styrene-divinylbenzene copolymers. These resins are preferably functionalized with halogen-free acid groups such as sulphonic, carboxylic, dicarboxylic, etc. (Encyclopedia of Chemical Technology Kirk Othmer 3rd Edition, Vol. 13, p 678-705, Wiley-Interscience, John Wiley and Sons, 1981). Furthermore the resins used in the present invention can have an inorganic part, e.g. the resin is deposited onto an inorganic solid.
In a particularly preferred embodiment, the hologen-free acid resin is a sulphonated styrene-divinylbenzene copolymer resin.
The catalyst of the first reaction comprises at least a noble metal or semi-noble metal selected from groups VII to XI of the periodic table supported on the above resin.
Preferably, said noble or semi-noble metal is selected from the group consisting of palladium, platinum, silver, gold, rhodium, iridium, ruthenium, osmium, and mixtures thereof. Most preferred metal is palladium, optionally in combination with other metal cited.
The catalyst is preferably prepared by adding a noble metal or semi-noble metal belonging to groups VII to XI of the periodic table, preferably palladium, platinum, silver, gold, rhodium, iridium, ruthenium, osmium, or mixtures of two or more of these metals, to the non-halogenated acid resin. The amount of metal supported can vary in a broad range, but is preferably comprised between 0.001 and 20% with respect to the non-halogenated acid resin, more preferably between 0.1 and 10%.
The addition of the metal to the support can be performed using any of the known preparation techniques of supported metal catalyst, e.g. impregnation, adsorption, ionic exchange, etc. For the impregnation, it is possible to use any kind of inorganic or organic salt of the metal to be impregnated that is soluble in the solvent used in the addition of the metal. Suitable salts are for example acetate, nitrate, halide, oxalate, etc.
In a particular embodiment, the first step comprises:
a) feeding to a reactor, containing the catalyst in a fixed bed or dispersed in a liquid medium:
a1) a liquid stream consisting of an alcohol or an alcohol-water mixture, and
a2) a gaseous stream containing hydrogen and oxygen, and optionally an inert gas, wherein the concentration of hydrogen is lower than 4.5% by volume: and
b) removing from the reactor:
b1) a liquid stream substantially consisting of the stream a1 and also the hydrogen peroxide and water produced by the reaction; and
b2) a gaseous stream consisting of the non-reacted gases and eventual inert gases.
When the first reaction is performed in a slurry reactor, the catalyst is preferably removed from the hydrogen peroxide solution stream using the techniques known in the art such as decantation, centrifugation, filtration, etc. In the preferred embodiment of the invention wherein the catalyst is used in fixed bed, obviously, the separation step is not necessary.
Although not necessary, in some cases it may be desirable to remove a portion of the solvent or water from the first reactor effluent to generate a more concentrated hydrogen peroxide solution.
The final non acidic hydrogen peroxide solution is passed on to a second catalytic reaction step.
Oxidation Step
The reaction mixture containing hydrogen peroxide from the hydrogen peroxide synthesis reaction is used as the oxidant for the oxidation reaction in which an organic compound undergoes oxidation by the hydrogen peroxide in the presence of a catalyst. The ability to use the reaction mixture from the first step directly as an ingredient of the second reaction, providing the peroxide for the oxidation, permits great advantages in efficiency and cost-effectiveness, since no intermediate step is required in order to purify the peroxide.
A variety of organic chemical compounds can be used in the overall process of the instant invention in order to produce the desired oxidized organic chemical compounds. Major classes of organic chemical compounds include aromatics, alkanes, carbonyl compounds and olefins, as well as compounds containing mixed functionality and heteroatoms such as sulfur or nitrogen, with the olefin compounds being preferred. The major groups of oxidized organic chemical compounds are alcohols, epoxides, carboxylic acids, hydroxylated aromatics, aldehydes/ketones, glycols, oximes and N-oxides.
Some important specific and preferred organic chemical compounds and their corresponding oxidized products which may be processed by the two-step selective catalytic oxidation process of this invention utilizing hydrogen peroxide intermediate as the oxidant are listed below;
Olefins are more preferred organic compounds, with propylene being the most preferred feedstock for producing propylene oxide.
The non acidic hydrogen peroxide solution obtained in the first step and an additional solvent, if it is desirable, are fed, preferably continuously, together with a selected organic chemical feedstock into a catalytic reactor, which may be a fixed bed or slurry-type reactor containing a known oxidation catalyst such as TS-1, TS-2, Tixcex2, Ti-MCM-41, titanium on amorphous silica, etc., or any known catalyst capable of oxidizing efficiently organic compounds with hydrogen peroxide. For a fixed bed reactor, the preferred catalyst particle size will be 0.5-20 mm, and for a fluidized or slurry reactor the preferred catalyst size will be 50-1,000 microns. The reactor is maintained at about xe2x88x9230xc2x0 C. to 200xc2x0 C. of temperature, preferably at xe2x88x9210xc2x0 C. to 100xc2x0 C. temperature. The oxidation reaction is carried out at a pressure, usually above atmospheric pressure, enough to keep the organic feedstock in the liquid phase. In a particular embodiment, the oxidation reaction is carried out at a pressure between 0.1 and 10 MPa, preferably, between 0.1 and 5 MPa. If the reactor is of the slurry type, the effluent liquid stream removed from the reactor will contain unreacted feedstocks, solvent and catalyst particles, and preferably the catalyst should be recovered by centrifugation, filtration or any adequate means and reused. For fixed bed reactors, no catalyst recovery and recycle is needed. Following any catalyst recovery, the remaining liquid stream is passed to organic feedstock recovery; this unreacted organic compound could be recycled back to the reactor together with make up feedstock supplied. The unreacted organic compound recovery step may be carried out in a single distillation tower or it may include sequential distillation towers operated at progressively lower pressures as desired.
The remaining stream is passed to product purification, where product is removed for further purification as desired. Solvents and any heavy fractions are passed to a solvent recovery unit. The solvent fed to the organic compound oxidation, if it is necessary, is recycled back to the oxidation reactor. The liquid solvent employed in the hydrogen peroxide solution are recycled back to the first step, while heavy fractions and the net water produced in reactor are withdrawn for other use or disposal.
Any useful process schemes or sequences for oxidized product purification and recovery are also possible as will be understood by those skilled in this art will be applied to this invention.
In order to illustrate the nature of the invention more fully, and the manner in which it is to be practiced, the following examples are presented:

Integrated process for selective oxidation of organic compounds


The present invention relates to methods for treatment or prevention of asthma, mild intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, eosinophilic asthma, neutrophilic asthma, steroid refractory asthma, status asthmaticus, pneumonia, bronchiectasis, COPD, sarcoidosis, and lung cancer based on reducing airway hyper responsiveness, increasing pulmonary compliance, reducing lung inflammation, reducing inflammatory cell count in bronchoalveolar fluid and reducing cytokine production by administration of a mammalian α- and/or β-defensin.

Asthma is a heterogenous inflammatory disorder of the airways characterized by chronic inflammation, airway hyper responsiveness, and by symptoms of recurrent wheezing, coughing, and shortness of breath. Asthma is a major public health problem affecting 300 million people worldwide, and has increased considerably in prevalence over the past three decades, particularly in the western world (Cosmi et al., 2011). The mechanisms of pathogenesis however, remain elusive. Steroids and combination therapies with long-acting β-agonists are the mainstay of asthma treatment. These therapies effectively suppress acute inflammatory symptoms and cytokine release but there are no preventions or cure of disease to date.
Mild to moderate allergic asthma is generally characterized by acute or chronic airway inflammation consisting of activated Th2 lymphocytes and eosinophil infiltrates in association with IgE production, mucus secreting cells, hyperplasia and metaplasia, remodeling of the airway wall and airway hyper responsiveness (AHR). The AHR is characterized by enhanced responsiveness and constriction of the airways to non-specific spasmogenic stimuli, such as methacholine (Hansbro et al., 2011). Th2 cells, through the secretion of their cytokines IL-3, IL-4, IL-5, IL-9, IL-13, amongst others, contribute to various pathological features of the disease.
Severe, neutrophilic or steroid refractory asthma has different pathological features to mild to moderate allergic asthma and is characterized by a mixed Th2/Th1 phenotype with a possible contribution of Th17 cells. Tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, IL-17 and IL-27 are elevated and may induce the influx of neutrophils (rather than eosinophils) or a mixed granulocytic airway infiltrate that is characteristic for this subtype of asthma. Patients with this subtype of asthma are refractory to glucocorticoid treatment and both bacterial and viral infections are implicated in the induction and progression of disease (Hansbro et al., 2004). Also, asthmatic patients and patients with atopic dermatitis are more likely to develop infections e.g. pneumonia compared with non-atopic individuals.
The concept of treating asthma by targeting a single cytokine e.g. anti IL-4; anti IL-5; anti TNF-α has had limited success. Indeed, steroid therapy, which is currently the mainstay therapy, is thought to act by suppressing a range of pro-inflammatory pathways (Hansbro et al, 2011).
Chronic obstructive pulmonary disease (COPD). COPD is a major public health problem projected to be the fourth leading cause of death worldwide by 2020. Although persistent inhalation of toxic particles and gases are the major risk factors, with tobacco smoking being the best example of this type of risk, only 15% of smokers develop COPD (Fletcher and Peto, 1977). Although smokers have a dysfunctional immune system (Bouloukaki et al., 2011), the development and increasing disease severity of COPD progressively worsens the inflammatory cell burden (Hogg et al., 2004).
Microbiome. Infant microbiota is initially uniform across various body sites, differing in subsequent days and weeks into site-specific communities. The lung microbiome of healthy adults is dominated by the phylae Bacteroidetes, Firmicutes, and Proteobacteria with the core microbiota consisting of Pseudomonas, Streptococcus, Prevotella, Fusobacteria, Veillonella, Haemophilus, Neisseria and Porphyromonas (Charlson et al, 2011). Among asthmatics an increased frequency of Proteobacteria (in particular Haemophilus, Moraxella and Neisseria) and Firmicutes (in particular Lactobacillus spp.) and decreased frequency of Bacteroidetes (in particular Prevotella) compared with controls has been observed (Hilty et al., 2010). Similarly epidemiological data show that gut microbiota differs between asthmatic and non-asthmatic infants (Penders et al., 2007).
Defensins
Defensins represent one of the dominant innate host defences that serve to maintain a healthy microbiome and ward off potential pathogens (Wehkamp et al, 2002 and Salzman et al, 2007). Defensins are peptides possessing antimicrobial activity against Gram positive and negative bacteria, fungi and archaea as well as anti-inflammatory activity. Defensins, and in particular hBD2 have shown therapeutic potential in the treatment of Inflammatory Bowel Disease (WO 2010/007166; WO 2013/007596).
In conclusion, there is a need for new treatments of subjects suffering from inflammatory conditions of the lung. There is a particular need for treatments that can be administered through the airways for patients that can themselves administer, e.g. inhale, the drugs, and there is a need for treatment via other administration routes to patients that are unable to inhale drugs efficiently.

Methods for treating inflammatory conditions of the lungs


Physiological effects have been observed in a human subject in response to stimulation of the skin with weak electromagnetic fields that are pulsed with certain frequencies near xc2xd Hz or 2.4 Hz, such as to excite a sensory resonance. Many computer monitors and TV tubes, when displaying pulsed images, emit pulsed electromagnetic fields of sufficient amplitudes to cause such excitation. It is therefore possible to manipulate the nervous system of a subject by pulsing images displayed on a nearby computer monitor or TV set. For the latter, the image pulsing may be imbedded in the program material, or it may be overlaid by modulating a video stream, either as an RF signal or as a video signal. The image displayed on a computer monitor may be pulsed effectively by a simple computer program. For certain monitors, pulsed electromagnetic fields capable of exciting sensory resonances in nearby subjects may be generated even as the displayed images are pulsed with subliminal intensity.

The invention relates to the stimulation of the human nervous system by an electromagnetic field applied externally to the body. A neurological effect of external electric fields has been mentioned by Wiener (1958), in a discussion of the bunching of brain waves through nonlinear interactions. The electric field was arranged to provide xe2x80x9ca direct electrical driving of the brainxe2x80x9d. Wiener describes the field as set up by a 10 Hz alternating voltage of 400 V applied in a room between ceiling and ground. Brennan (1992) describes in U.S. Pat. No. 5,169,380 an apparatus for alleviating disruptions in circadian rythms of a mammal, in which an alternating electric field is applied across the head of the subject by two electrodes placed a short distance from the skin.
A device involving a field electrode as well as a contact electrode is the xe2x80x9cGraham Potentializerxe2x80x9d mentioned by Hutchison (1991). This relaxation device uses motion, light and sound as well as an alternating electric field applied mainly to the head. The contact electrode is a metal bar in Ohmic contact with the bare feet of the subject, and the field electrode is a hemispherical metal headpiece placed several inches from the subject""s head.
In these three electric stimulation methods the external electric field is applied predominantly to the head, so that electric currents are induced in the brain in the physical manner governed by electrodynamics. Such currents can be largely avoided by applying the field not to the head, but rather to skin areas away from the head. Certain cutaneous receptors may then be stimulated and they would provide a signal input into the brain along the natural pathways of afferent nerves. It has been found that, indeed, physiological effects can be induced in this manner by very weak electric fields, if they are pulsed with a frequency near xc2xd Hz. The observed effects include ptosis of the eyelids, relaxation, drowziness, the feeling of pressure at a centered spot on the lower edge of the brow, seeing moving patterns of dark purple and greenish yellow with the eyes closed, a tonic smile, a tense feeling in the stomach, sudden loose stool, and sexual excitement, depending on the precise frequency used, and the skin area to which the field is applied. The sharp frequency dependence suggests involvement of a resonance mechanism.
It has been found that the resonance can be excited not only by externally applied pulsed electric fields, as discussed in U.S. Pat. Nos. 5,782,874, 5,899,922, 6,081,744, and 6,167,304, but also by pulsed magnetic fields, as described in U.S. Pat. Nos. 5,935,054 and 6,238,333, by weak heat pulses applied to the skin, as discussed in U.S. Pat. Nos. 5,800,481 and 6,091,994, and by subliminal acoustic pulses, as described in U.S. Pat. No. 6,017,302. Since the resonance is excited through sensory pathways, it is called a sensory resonance. In addition to the resonance near xc2xd Hz, a sensory resonance has been found near 2.4 Hz. The latter is characterized by the slowing of certain cortical processes, as discussed in the ""481, ""922, ""302, ""744, ""944, and ""304 patents.
The excitation of sensory resonances through weak heat pulses applied to the skin provides a clue about what is going on neurologically. Cutaneous temperature-sensing receptors are known to fire spontaneously. These nerves spike somewhat randomly around an average rate that depends on skin temperature. Weak heat pulses delivered to the skin in periodic fashion will therefore cause a slight frequency modulation (fm) in the spike patterns generated by the nerves. Since stimulation through other sensory modalities results in similar physiological effects, it is believed that frequency modulation of spontaneous afferent neural spiking patterns occurs there as well.
It is instructive to apply this notion to the stimulation by weak electric field pulses administered to the skin. The externally generated fields induce electric current pulses in the underlying tissue, but the current density is much too small for firing an otherwise quiescent nerve. However, in experiments with adapting stretch receptors of the crayfish, Terzuolo and Bullock (1956) have observed that very small electric fields can suffice for modulating the firing of already active nerves. Such a modulation may occur in the electric field stimulation under discussion.
Further understanding may be gained by considering the electric charges that accumulate on the skin as a result of the induced tissue currents. Ignoring thermodynamics, one would expect the accumulated polarization charges to be confined strictly to the outer surface of the skin. But charge density is caused by a slight excess in positive or negative ions, and thermal motion distributes the ions through a thin layer. This implies that the externally applied electric field actually penetrates a short distance into the tissue, instead of stopping abruptly at the outer skin surface. In this manner a considerable fraction of the applied field may be brought to bear on some cutaneous nerve endings, so that a slight modulation of the type noted by Terzuolo and Bullock may indeed occur.
The mentioned physiological effects are observed only when the strength of the electric field on the skin lies in a certain range, called the effective intensity window. There also is a bulk effect, in that weaker fields suffice when the field is applied to a larger skin area. These effects are discussed in detail in the ""922 patent.
Since the spontaneous spiking of the nerves is rather random and the frequency modulation induced by the pulsed field is very shallow, the signal to noise ratio (S/N) for the fm signal contained in the spike trains along the afferent nerves is so small as to make recovery of the fm signal from a single nerve fiber impossibile. But application of the field over a large skin area causes simultaneous stimulation of many cutaneous nerves, and the fm modulation is then coherent from nerve to nerve. Therefore, if the afferent signals are somehow summed in the brain, the fm modulations add while the spikes from different nerves mix and interlace. In this manner the S/N can be increased by appropriate neural processing. The matter is discussed in detail in the ""874 patent. Another increase in sensitivity is due to involving a resonance mechanism, wherein considerable neural circuit oscillations can result from weak excitations.
An easily detectable physiological effect of an excited xc2xd Hz sensory resonance is ptosis of the eyelids. As discussed in the ""922 patent, the ptosis test involves first closing the eyes about half way. Holding this eyelid position, the eyes are rolled upward, while giving up voluntary control of the eyelids. The eyelid position is then determined by the state of the autonomic nervous system. Furthermore, the pressure excerted on the eyeballs by the partially closed eyelids increases parasympathetic activity. The eyelid position thereby becomes somewhat labile, as manifested by a slight flutter. The labile state is sensitive to very small shifts in autonomic state. The ptosis influences the extent to which the pupil is hooded by the eyelid, and thus how much light is admitted to the eye. Hence, the depth of the ptosis is seen by the subject, and can be graded on a scale from 0 to 10.
In the initial stages of the excitation of the xc2xd Hz sensory resonance, a downward drift is detected in the ptosis frequency, defined as the stimulation frequency for which maximum ptosis is obtained. This drift is believed to be caused by changes in the chemical milieu of the resonating neural circuits. It is thought that the resonance causes perturbations of chemical concentrations somewhere in the brain, and that these perturbations spread by diffusion to nearby resonating circuits. This effect, called xe2x80x9cchemical detuningxe2x80x9d, can be so strong that ptosis is lost altogether when the stimulation frequency is kept constant in the initial stages of the excitation. Since the stimulation then falls somewhat out of tune, the resonance decreases in amplitude and chemical detuning eventually diminishes. This causes the ptosis frequency to shift back up, so that the stimulation is more in tune and the ptosis can develop again. As a result, for fixed stimulation frequencies in a certain range, the ptosis slowly cycles with a frequency of several minutes. The matter is discussed in the ""302 patent.
The stimulation frequencies at which specific physiological effects occur depend somewhat on the autonomic nervous system state, and probably on the endocrine state as well.
Weak magnetic fields that are pulsed with a sensory resonance frequency can induce the same physiological effects as pulsed electric fields. Unlike the latter however, the magnetic fields penetrate biological tissue with nearly undiminished strength. Eddy currents in the tissue drive electric charges to the skin, where the charge distributions are subject to thermal smearing in much the same way as in electric field stimulation, so that the same physiological effects develop. Details are discussed in the ""054 patent.
Computer monotors and TV monitors can be made to emit weak low-frequency electromagnetic fields merely by pulsing the intensity of displayed images. Experiments have shown that the xc2xd Hz sensory resonance can be excited in this manner in a subject near the monitor. The 2.4 Hz sensory resonance can also be excited in this fashion. Hence, a TV monitor or computer monitor can be used to manipulate the nervous system of nearby people.
The implementations of the invention are adapted to the source of video stream that drives the monitor, be it a computer program, a TV broadcast, a video tape or a digital video disc (DVD).
For a computer monitor, the image pulses can be produced by a suitable computer program. The pulse frequency may be controlled through keyboard input, so that the subject can tune to an individual sensory resonance frequency. The pulse amplitude can be controlled as well in this manner. A program written in Visual Basic(R) is particularly suitable for use on computers that run the Windows 95(R) or Windows 98(R) operating system. The structure of such a program is described. Production of periodic pulses requires an accurate timing procedure. Such a procedure is constructed from the GetTimeCount function available in the Application Program Interface (API) of the Windows operating system, together with an extrapolation procedure that improves the timing accuracy.
Pulse variability can be introduced through software, for the purpose of thwarting habituation of the nervous system to the field stimulation, or when the precise resonance frequency is not known. The variability may be a pseudo-random variation within a narrow interval, or it can take the form of a frequency or amplitude sweep in time. The pulse variability may be under control of the subject.
The program that causes a monitor to display a pulsing image may be run on a remote computer that is connected to the user computer by a link; the latter may partly belong to a network, which may be the Internet.
For a TV monitor, the image pulsing may be inherent in the video stream as it flows from the video source, or else the stream may be modulated such as to overlay the pulsing. In the first case, a live TV broadcast can be arranged to have the feature imbedded simply by slightly pulsing the illumination of the scene that is being broadcast. This method can of course also be used in making movies and recording video tapes and DVDs.
Video tapes can be edited such as to overlay the pulsing by means of modulating hardware. A simple modulator is discussed wherein the luminance signal of composite video is pulsed without affecting the chroma signal. The same effect may be introduced at the consumer end, by modulating the video stream that is produced by the video source. A DVD can be edited through software, by introducing pulse-like variations in the digital RGB signals. Image intensity pulses can be overlaid onto the analog component video output of a DVD player by modulating the luminance signal component. Before entering the TV set, a television signal can be modulated such as to cause pulsing of the image intensity by means of a variable delay line that is connected to a pulse generator.
Certain monitors can emit electromagnetic field pulses that excite a sensory resonance in a nearby subject, through image pulses that are so weak as to be subliminal. This is unfortunate since it opens a way for mischievous application of the invention, whereby people are exposed unknowingly to manipulation of their nervous systems for someone else""s purposes. Such application would be unethical and is of course not advocated. It is mentioned here in order to alert the public to the possibility of covert abuse that may occur while being online, or while watching TV, a video, or a DVD.

Nervous system manipulation by electromagnetic fields from monitors


The downstream end of the flow trim cage is formed to provide an inwardly protruding lip. The lip deflects flow inwardly as it leaves the bore of the cage. As a result, erosion of the body, immediately downstream of the flow trim, is reduced.

The present invention relates to a choke valve for controlling pressurized fluid flow through a line, such as the flow produced by an oil or gas well. More particularly the invention relates to modifying the outlet of the valve and its flow trim cage to thereby reduce erosion of the valve body immediately downstream of the cage.
A choke valve (hereinafter referred to as a xe2x80x98chokexe2x80x99) is a throttling device. It is used to control flow rate while reducing the fluid pressure of a stream moving through a flow line. Chokes are commonly used in oil or gas drilling and production systems to provide throttling and shut-off with respect to high pressure streams.
The present invention was developed in connection with seeking to ameliorate the erosive effect of such streams when carrying abrasive solid particles, such as entrained sand.
A choke, previously developed by the assignee of this application, is disclosed in U.S. Pat. No. 6,105,614. This choke is illustrated in FIG. 1 of this specification. In general, the choke comprises:
a valve body a having a T-shaped bore structure consisting of an inlet bore b, an outlet bore c and a component bore d;
the choke internals are positioned in the component bore d, which communicates with the inlet and outlet bores b, c. The internals comprise a flow trim e, having a tubular cylindrical cage f, whose side wall g forms ports h, and a tubular cylindrical sleeve i for sliding along the cage f, together with means j for advancing or retracting the sleeve and suitable sealing means k.
In the operation of the choke, the flow stream moves through an L-shaped passageway formed by the body inlet bore b, the cage ports h, the cage bore 1, and the body outlet bore c. The sleeve i functions to throttle flow by adjusting the area of the ports h.
It will be noted that the valve body outlet bore c has a reduced diameter section m, an expanding diameter transition section n and a full diameter section o which corresponds with the internal diameter of the downstream flow line (not shown).
In the course of passing through the choke, the velocity of the stream increases. This occurs because the passageway cross-sectional areas in the choke are smaller than the bore cross-sectional area of the flow lines upstream and downstream of the choke. This acceleration exacerbates erosive effects on the choke.
The valve body of the choke typically is made of relatively softer steel, to permit the body to be machined. In contrast, the flow trim is made of harder material, to better resist erosion as the stream makes a right angle turn through the flow trim.
Our inspection of used chokes has shown that severe erosion of the valve body commonly occurs along the reduced diameter section m of the valve outlet bore c, immediately downstream of the cage f.
It is the objective of the present invention to improve the choke""s ability to withstand erosion downstream of the flow trim.
As a result of experimental work involving test runs of pressurized fluid through a choke, we have discovered:
that provision of an annular, inwardly protruding lip at the outlet of the cage bore will deflect the fluid flow inwardly so as to reduce erosion of the valve body along the reduced diameter section of the outlet bore; and
that preferred conditions in this connection are:
(1) that the lip should protrude inwardly less than about 0.060 inches relative to the surface of the valve body outlet bore reduced diameter section;
(2) that the transition section of the valve body outlet bore should be spaced at least 0.5 inches and less than 1.125 inches from the cage bore outlet;
(3) that the lip should be formed as an inclined ramp having an inclination of about 10xc2x0; and
(4) the transition angle between the reduced diameter section of the outlet bore and the full diameter section should be in the range of 25xc2x0-35xc2x0. [To match the fluid re-entry angle thereby reducing erosion to the transition area between bore m and bore o.]
If any of these limitations are not met, then there is a tendency to create eddy currents at the valve body surface of the reduced diameter section of the outlet bore, with some consequent erosion.
Broadly stated, the invention is directed to a choke valve for controlling pressurized fluid flow in a line, comprising: a valve body forming an inlet bore, a component bore and an outlet bore; each bore having an inlet and an outlet; the component bore connecting the outlet of the inlet bore and the inlet of the outlet bore; a flow trim positioned in the component bore for controlling flow through the bores, said flow trim comprising a tubular cage having upstream and downstream ends, said cage having a side wall with an inner surface forming a longitudinal bore, said cage side wall forming flow ports extending therethrough at its upstream end, and a tubular sleeve operative to slide along the cage to throttle the ports; means, extending into the component bore, for biasing the sleeve along the cage; means for sealing the flow trim and biasing means within the component bore; the cage being formed of harder material than the body; the cage side wall forming an inwardly protruding lip at the downstream end of the cage bore for deflecting fluid passing through the valve toward the center of the valve body outlet bore to thereby reduce erosion of the valve body immediately downstream of the cage.